An interesting diagnosis for a presacral mass: case report

A presacral mass can present a diagnostic dilemma for the surgical oncologist. Differential diagnoses include congenital causes such as teratoma or chordoma, neurological causes such as neurilemoma or neurofibroma or other malignancies such as lymphoma or sarcoma. Diagnosis usually requires imaging such as CT and MRI and tissue biopsy. We present an unusual cause of a presacral mass being extramedullary haematopoiesis, found incidentally in a 71 year old female. Extramedullary haematopoiesis is defined as the production of myeloid and erythroid elements outside of the bone-marrow. This diagnosis is extremely rare in the presacral area especially in a patient with no haematological abnormalities. A review of the literature is presented

Osteosarcoma: From Molecular Biology to Mesenchymal Stem Cells

Osteosarcoma is the most common primary malignant tumour of bone. Currently, despite treatment with multi-agent chemotherapy and limb salvage surgery, the five-year survival rate for osteosarcoma remains at 70%. The pathogenesis of osteosarcoma is complex and involves alterations in cellular apoptosis, adhesion, migration, invasion and molecular signalling. Research most recently has focused on the molecular basis of the disease with the goal of identifying novel therapeutic targets. To this end, mesenchymal stem cells (MSCs) have been identified to play a role in sarcomagenesis. MSC transformation may give rise to tumours, whereas interactions of MSCs with osteosarcoma cells in the tumour microenvironment may cause increased cell proliferation. This is in stark contrast to the role of MSCs as a promising source for tissue repair and regeneration. In order to utilize MSCs for biological reconstruction in the setting of osteosarcoma, further research is necessary to delineate the role of MSCs in osteosarcoma transformation and progression

Efficacy of Continuously Administered PEDF-Derived Synthetic Peptides against Osteosarcoma Growth and Metastasis

The potent antiangiogenic pigment epithelium-derived factor (PEDF) has shown promise against osteosarcoma, a tumour that originates in the bone and metastasises to the lungs. Neurotrophic, antiangiogenic, antiproliferative, and antimetastatic properties of PEDF have been attributed to a number of functional epitopes on the PEDF glycoprotein. StVOrth-2 (residues 78–102) and StVOrth-3 (residues 90–114) are two PEDF-derived peptides based on these functional epitopes. StVOrth-2 has previously been shown to inhibit osteosarcoma cell proliferation, while StVOrth-3 increased osteosarcoma cell adhesion to collagen I in vitro. In this paper, we have evaluated systemically and continuously delivered StVOrth-2 and StVOrth-3 using a clinically relevant murine model of osteosarcoma with spontaneous metastasis. Treatment with StVOrth-2 or StVOrth-3 with microosmotic pumps was initiated after primary osteosarcoma was established in the tibia. While treatment with StVOrth-2 and StVOrth-3 did not appear to affect local tumour invasion, tumour necrosis or apoptosis, StVOrth-2 predominantly restricted the growth of primary tumours, while StVOrth-3 restricted the burden of pulmonary metastatic disease. No peptide caused gross toxicity in mouse tissues as assessed by measuring weight of animals, serum biochemistry, and gross tissue observation. The differential effects exhibited by StVOrth-2 and StVOrth-3 in this orthotopic model of osteosarcoma may be related to the functional epitopes on the PEDF glycoprotein that they represent

Combined Analysis on the Effects of Late Gestation Supplementation in a Spring Calving Beef Herd

Data were compiled from 4 independent studies conducted over 13 years in the Nebraska Sandhills. Th is combined analysis evaluated the effects of late gestation supplementation on cow and calf productivity in a spring calving herd. Cows wintered on dormant range, sub- irrigated meadow or corn residue. Late gestation supplementation improved pregnancy rates regardless of supplement amount or over winter treatment. Supplement did not affect cow body weight and condition score. Calves born to cows fed supplement had greater weaning weights regardless of when they were weaned

The Molecular Pathogenesis of Osteosarcoma: A Review

Osteosarcoma is the most common primary malignancy of bone. It arises in bone during periods of rapid growth and primarily affects adolescents and young adults. The 5-year survival rate for osteosarcoma is 60%–70%, with no significant improvements in prognosis since the advent of multiagent chemotherapy. Diagnosis, staging, and surgical management of osteosarcoma remain focused on our anatomical understanding of the disease. As our knowledge of the molecular pathogenesis of osteosarcoma expands, potential therapeutic targets are being identified. A comprehensive understanding of these mechanisms is essential if we are to improve the prognosis of patients with osteosarcoma through tumour-targeted therapies. This paper will outline the pathogenic mechanisms of osteosarcoma oncogenesis and progression and will discuss some of the more frontline translational studies performed to date in search of novel, safer, and more targeted drugs for disease management

Clinical Features of High-Grade Extremity and Trunk Sarcomas in Patients Aged 80 Years and Older: Why Are Outcomes Inferior?

Background: The population of many countries is aging and a significant number of elderly patients with soft-tissue sarcoma are being seen at cancer centers. The unique therapeutic and prognostic implications of treating soft-tissue sarcoma in geriatric patients warrant further consideration in order to optimize outcomes.Patients and Methods: This is a single-institution retrospective study of consecutive non-metastatic primary extremity and trunk high-grade sarcomas surgically treated between 1996 and 2012, with at least 2 years of follow-up for survivors. Patient characteristics and oncological outcomes were compared between age groups (≥80 vs. <80 years), using Chi-square or Fisher-exact test and Log-Rank or Wilcoxon test, respectively. Deaths from other causes were censored for disease-specific survival estimation. A p< 0.05 was regarded as statistically significant.Results: A total of 333 cases were eligible for this study. Thirty-six patients (11%) were aged ≥80 years. Unplanned surgery incidence and surgical margin status were comparable between the age groups. Five-year local-recurrence-free, metastasis-free and disease-specific survivals were 72% (≥80 years) vs. 90% (<80 years) (p = 0.004), 59 vs. 70% (p = 0.07) and 55 vs. 80% (p < 0.001), respectively. A significantly earlier first metastasis after surgery (8.3 months vs. 20.5 months, mean) and poorer survival after first metastasis (p = 0.03) were observed. Cox analysis revealed “age ≥80 years” as an independent risk factor for local failure and disease-specific mortality, with hazard ratios of 2.41 (95% CI: 1.09–5.32) and 2.52 (1.33–4.13), respectively. A competing risks analysis also showed that “age ≥80 years” was significantly associated with the disease-specific mortality.Conclusions: Oncological outcomes were significantly worse in high-grade sarcoma patients aged ≥80 years. The findings of more frequent local failure regardless of a consistent primary treatment strategy, an earlier time to first metastasis after surgery, and poorer prognosis after first metastasis suggest that more aggressive tumor biology, in addition to multiple co-morbidity, may explain the inferiority

Safety, immunogenicity, and reactogenicity of BNT162b2 and mRNA-1273 COVID-19 vaccines given as fourth-dose boosters following two doses of ChAdOx1 nCoV-19 or BNT162b2 and a third dose of BNT162b2 (COV-BOOST): a multicentre, blinded, phase 2, randomised trial

Background Some high-income countries have deployed fourth doses of COVID-19 vaccines, but the clinical need, effectiveness, timing, and dose of a fourth dose remain uncertain. We aimed to investigate the safety, reactogenicity, and immunogenicity of fourth-dose boosters against COVID-19.Methods The COV-BOOST trial is a multicentre, blinded, phase 2, randomised controlled trial of seven COVID-19 vaccines given as third-dose boosters at 18 sites in the UK. This sub-study enrolled participants who had received BNT162b2 (Pfizer-BioNTech) as their third dose in COV-BOOST and randomly assigned them (1:1) to receive a fourth dose of either BNT162b2 (30 µg in 0·30 mL; full dose) or mRNA-1273 (Moderna; 50 µg in 0·25 mL; half dose) via intramuscular injection into the upper arm. The computer-generated randomisation list was created by the study statisticians with random block sizes of two or four. Participants and all study staff not delivering the vaccines were masked to treatment allocation. The coprimary outcomes were safety and reactogenicity, and immunogenicity (antispike protein IgG titres by ELISA and cellular immune response by ELISpot). We compared immunogenicity at 28 days after the third dose versus 14 days after the fourth dose and at day 0 versus day 14 relative to the fourth dose. Safety and reactogenicity were assessed in the per-protocol population, which comprised all participants who received a fourth-dose booster regardless of their SARS-CoV-2 serostatus. Immunogenicity was primarily analysed in a modified intention-to-treat population comprising seronegative participants who had received a fourth-dose booster and had available endpoint data. This trial is registered with ISRCTN, 73765130, and is ongoing.Findings Between Jan 11 and Jan 25, 2022, 166 participants were screened, randomly assigned, and received either full-dose BNT162b2 (n=83) or half-dose mRNA-1273 (n=83) as a fourth dose. The median age of these participants was 70·1 years (IQR 51·6–77·5) and 86 (52%) of 166 participants were female and 80 (48%) were male. The median interval between the third and fourth doses was 208·5 days (IQR 203·3–214·8). Pain was the most common local solicited adverse event and fatigue was the most common systemic solicited adverse event after BNT162b2 or mRNA-1273 booster doses. None of three serious adverse events reported after a fourth dose with BNT162b2 were related to the study vaccine. In the BNT162b2 group, geometric mean anti-spike protein IgG concentration at day 28 after the third dose was 23 325 ELISA laboratory units (ELU)/mL (95% CI 20 030–27 162), which increased to 37 460 ELU/mL (31 996–43 857) at day 14 after the fourth dose, representing a significant fold change (geometric mean 1·59, 95% CI 1·41–1·78). There was a significant increase in geometric mean anti-spike protein IgG concentration from 28 days after the third dose (25 317 ELU/mL, 95% CI 20 996–30 528) to 14 days after a fourth dose of mRNA-1273 (54 936 ELU/mL, 46 826–64 452), with a geometric mean fold change of 2·19 (1·90–2·52). The fold changes in anti-spike protein IgG titres from before (day 0) to after (day 14) the fourth dose were 12·19 (95% CI 10·37–14·32) and 15·90 (12·92–19·58) in the BNT162b2 and mRNA-1273 groups, respectively. T-cell responses were also boosted after the fourth dose (eg, the fold changes for the wild-type variant from before to after the fourth dose were 7·32 [95% CI 3·24–16·54] in the BNT162b2 group and 6·22 [3·90–9·92] in the mRNA-1273 group).Interpretation Fourth-dose COVID-19 mRNA booster vaccines are well tolerated and boost cellular and humoral immunity. Peak responses after the fourth dose were similar to, and possibly better than, peak responses after the third dose

Investigating novel therapies for osteosarcoma using advanced medical imaging

© 2012 Dr. Matthew L. BroadheadPublications included in thesis:Dowsey, M. M., Broadhead, M. L., Stoney, J. D. & Choong, P. F. (2009). Outcomes of total knee arthroplasty in English-versus non-English-speaking patients. Journal of Orthopaedic Surgery, 17(3), 305–309.Broadhead, M. L., Dass, C. R. & Choong, P. F. M. (2011). Systemically administered PEDF against primary and secondary tumours in a clinically relevant osteosarcoma model. British Journal of Cancer, 105(10), 1503–1511. DOI: 10.1038/bjc.2011.410Broadhead, M. L., Choong, P. F. M. & Dass, C. R. (2012). Efficacy of continuously administered PEDF-derived synthetic peptides against osteosarcoma growth and metastasis. Journal of Biomedicine and Biotechnology, 2012. DOI: 10.1155/2012/230298Broadhead, M. L., Dass, C. R. & Choong, P. F. M. (2009). Cancer cell apoptotic pathways mediated by PEDF: prospects for therapy. Trends in Molecular Medicine, 15(10), 461–467. DOI: 10.1016/j.molmed.2009.08.003Broadhead, M. L., Dass, C. R. & Choong, P. F. M. (2009). In vitro and in vivo biological activity of PEDF against a range of tumours. Expert Opinion on Therapeutic Targets, 13(12), 1429–1438. DOI: 10.1517/14728220903307475Broadhead, M. L., Clark, J. C. M., Choong, P. F. M. & Dass, C. R. (2010). Making gene therapy for osteosarcoma a reality. Expert Review of Anticancer Therapy, 10(4), 477–480. DOI: 10.1586/ERA.10.18Broadhead, M. L., Akiyama, T., Choong, P. F. M. & Dass, C. R. (2010). The pathophysiological role of PEDF in bone diseases. Current Molecular Medicine, 10(3), 296–301.Broadhead, M. L., Becerra, S. P., Choong, P. F. M. & Dass, C. R. (2010). The applied biochemistry of PEDF and implications for tissue homeostasis. Growth Factors, 28(4), 280–285. DOI: 10.3109/08977191003604513Broadhead, M. L., Clark, J. C. M., Dass, C. R. & Choong, P. F. M. (2010). Microarray: an instrument for cancer surgeons of the future? ANZ Journal of Surgery, 80(7-8), 531–536. DOI: 10.1111/j.1445-2197.2010.05379.xBroadhead, M. L., Clark, J. C. M., Myers, D. E., Dass, C. R. & Choong, P. F. M. (2011). The molecular pathogenesis of osteosarcoma: a review. Sarcoma, 2011. DOI: 10.1155/2011/959248Broadhead, M. L., Clark, J. C. M., Dass, C. R., Choong, P. F. M. & Myers, D. E. (2011). Therapeutic targeting of osteoclast function and pathways. Expert Opinion on Therapeutic Targets, 15(2), 169–181. DOI: 10.1517/14728222.2011.546351Babazadeh, S., Broadhead, M. L., Slavin, J. L. & Choong, P. F. M. (2009). An interesting diagnosis for a presacral mass: case report. International Seminars in Surgical Oncology, 6(18). DOI: 10.1186/1477-7800-6-18Babazadeh, S., Broadhead, M. L., Slavin, J. L., Schlicht, S. M. & Choong, P. F. M. (2010). Giant cell tumour of metacarpal diaphysis. European Journal of Radiology Extra, 75(1), e31–e36. DOI: 10.1016/j.ejrex.2010.04.008Broadhead, M. L., Babazadeh, S., O'Brien, B. & Choong, P. F. M. (2010). Thigh enlargement and the art of misdirection. ANZ Journal of Surgery, 80(11), 839–840. DOI: 10.1111/j.1445-2197.2010.05503.xBroadhead, M. L., Babazadeh, S., Goldwasser, M. & Choong, P. F. M. (2011). Waxing and waning of joint motion. Grand Rounds, 11, 44–47. DOI: 10.1102/1470-5206.2011.0011Babazadeh, S., Broadhead, M. L. & Choong, P. F. M. (2011). If you are called to lead, you are called to serve. ANZ Journal of Surgery, 81(6), 401–403. DOI: 10.1111/j.1445-2197.2011.05782.xBroadhead, M. L., Babazadeh, S., Ng, K. W., Choong, P. F. M. & Stoney, J. D. (2011). Atraumatic bilateral femoral neck fractures during pregnancy: a missed diagnosis. Australian and New Zealand Journal of Obstetrics and Gynaecology, 51(6), 563-564. DOI: 10.1111/j.1479-828X.2011.01366.xBabazadeh, S., Broadhead, M. L., Schlicht, S. M., Powell, G. J. & Tymms, G. M. (2011). Pathologic fracture of a calcaneal aneurysmal bone cyst. The Journal of Foot and Ankle Surgery, 50(6), 727–732. DOI: 10.1053/j.jfas.2011.04.036Osteosarcoma is the most common primary cancer of bone. Current best treatment consists of chemotherapy and surgery, however many tumours are chemoresistant. Spread of osteosarcoma to the lungs is frequent and is the most common cause of death. This thesis examines the role of pigment epithelium-derived factor (PEDF) in the processes of osteosarcoma growth, invasion and metastasis. In order to evaluate this potential role, both in vitro and in vivo studies have been performed. In vitro studies have examined the biological effects and mechanisms of PEDF. PEDF exhibits a multifaceted ability to inhibit osteosarcoma tumorigenicity. PEDF inhibits proliferation, induces apoptosis and reduces cell cycling of osteosarcoma cells in vitro. Additionally, the metastatic capacity of osteosarcoma cell lines is diminished by PEDF. Osteosarcoma cells treated with PEDF demonstrate an enhanced capacity for adhesion and a reduced ability for invasion through collagen I, the most abundant protein in bone. An established murine model of orthotopic osteosarcoma has been optimised for the evaluation of novel therapeutic agents in vivo. This model allowed for an evaluation of systemically delivered PEDF and PEDF-derived peptides, both as sole treatments and in combination with doxorubicin. Systemic administration of PEDF causes a reduction in both primary tumour volume and pulmonary metastatic disease. PEDF-derived peptides, StVOrth-2 (residues 78-102) and StVOrth-3 (residues 90-114) were also delivered systemically. StVOrth-2 primarily restricts growth of primary osteosarcoma while StVOrth-3 restricts pulmonary metastatic disease. Finally, advanced medical imaging techniques have been applied to this murine model of orthotopic osteosarcoma for the study of tumour growth, invasion and metastasis; in vivo bioluminescent imaging, [18F]-Fluoride-PET, [18F]-FDG-PET and micro-computed tomography provide novel information about this model. Use of these imaging modalities has improved osteosarcoma modelling and allowed closer monitoring of disease progression. This is the first time that in vivo imaging has been used in the assessment of PEDF’s anti-osteosarcoma properties and is a major advance from previously published studies demonstrating direct effects on osteosarcoma growth and metastasis

Combined Analysis on the Effects of Late Gestation Supplementation in a Spring Calving Beef Herd

Data were compiled from 4 independent studies conducted over 13 years in the Nebraska Sandhills. Th is combined analysis evaluated the effects of late gestation supplementation on cow and calf productivity in a spring calving herd. Cows wintered on dormant range, sub- irrigated meadow or corn residue. Late gestation supplementation improved pregnancy rates regardless of supplement amount or over winter treatment. Supplement did not affect cow body weight and condition score. Calves born to cows fed supplement had greater weaning weights regardless of when they were weaned